Kinetic Modeling of API Oxidation: (2) Imipramine Stress Testing.

Area of Science:

• Pharmaceutical Chemistry
• Computational Chemistry
• Chemical Kinetics

Background:

• Active pharmaceutical ingredient (API) chemical stability is crucial for drug safety and efficacy.
• Traditional stress testing for API stability is time-consuming and resource-intensive, especially in early drug development.
• Computational methods offer a potential solution for accelerated screening and enhanced stability studies.

Purpose of the Study:

• To develop and validate an ab initio predictive chemical kinetic model for API degradation.
• To investigate the free-radical oxidative degradation of imipramine.
• To compare computational predictions with experimental observations for API stress testing.

Main Methods:

• Utilized quantum chemical calculations and automated reaction mechanism generation.
• Developed an ab initio predictive chemical kinetic model for oxidative degradation.
• Conducted stress testing of imipramine in an azobis(isobutyronitrile) (AIBN) solution and compared with model predictions.

Main Results:

• The ab initio kinetic model successfully predicted the two major imipramine degradation products, iminodibenzyl and desimipramine.
• The model identified these key products within its top three predicted degradation products.
• Demonstrated the utility of predictive kinetic modeling in understanding API degradation pathways.

Conclusions:

• Ab initio chemical kinetic modeling combined with quantum chemical computations can effectively elucidate API chemical stability issues.
• This approach has the potential to significantly accelerate drug development and reduce costs.
• An automated digital workflow integrating first-principle models with data-driven methods and high-throughput experiments could transform API stability studies.